DESCRIPTION:(Adapted from investigator's abstract) The overall goal of this research proposal is to delineate the function of the LCR of the beta-globin locus using both molecular and biophysical approaches. The questions being addressed include whether the beta-globin LCR physically interacts with the individual globin gene promoters, and what the correlation is between these interactions and globin gene transcription. The proposal has three specific aims. The first specific aim will involve the production of a partially "humanized" mouse in which one copy of the murine beta-globin locus will be replaced with a human beta-globin locus using cre-lox site-specific recombination technology and embryonic stem cells. This will fulfill the criteria of a single copy intact locus that can be reproducibly integrated into the same chromosomal location where the chromatin is conducive to globin gene expression. Specific Aim 2 involves tests of the physical interaction of the LCR with the human globin gene using fluorescence resonance energy transfer (FRET). Specific Aim 3 will test the role of the LCR sequences in LCR complex formation and globin gene regulation using transgenic mice containing mutant beta-globin loci by applying FRET.